NMDA receptor activations produce substantial elevations in intracellular calcium levels, which initiate signaling cascades critical for normal ad pathological brain processes. These include normal synaptic development and plasticity, as well as psychiatric conditions such as addiction and chronic pain, schizophrenia, and neuropathologies such as stroke and Alzheimer's disease. Until recently it was assumed that the amount of calcium in the NMDA receptor current is fixed and controlled solely by gating modulators and channel blockers. This project investigates a newly reported modulatory mechanism by which intracellular signaling cascades can change in a reversible fashion the amount of calcium in the NMDA receptor current. This work seeks to identify the molecular determinants and mechanisms responsible for this new modulation. The resulting knowledge will inform novel strategies to address dysfunctions and pathologies where NMDA receptor- mediated calcium is a cause or an aggravating factor.